title: Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation.
abstract: The hallmark of Alzheimer's disease (AD) pathology is an accumulation of amyloid β (Aβ) and phosphorylated tau, which are encoded by the amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) genes, respectively. Less than 5% of all AD cases are familial in nature, i.e. caused by mutations in APP, PSEN1 or PSEN2. Almost all mutations found in them are related to an overproduction of Aβ1-42, which is prone to aggregation. While these genes are mutation free, their function, or those of related genes, could be compromised in sporadic AD as well. In this study, pyrosequencing analysis of post-mortem brains revealed aberrant CpG methylation in APP, MAPT and GSK3B genes of the AD brain. These changes were further evaluated by a newly developed in vitro-specific DNA methylation system, which in turn highlighted an enhanced expression of APP and MAPT. Cell nucleus sorting of post-mortem brains revealed that the methylation changes of APP and MAPT occurred in both neuronal and non-neuronal cells, whereas GSK3B was abnormally methylated in non-neuronal cells. Further analysis revealed an association between abnormal APP CpG methylation and apolipoprotein E ε4 allele (APOE ε4)-negative cases. The presence of a small number of highly methylated neurons among normal neurons contribute to the methylation difference in APP and MAPT CpGs, thus abnormally methylated cells could compromise the neural circuit and/or serve as 'seed cells' for abnormal protein propagation. Our results provide a link between familial AD genes and sporadic neuropathology, thus emphasizing an epigenetic pathomechanism for sporadic AD.
authors.affiliation: Department of Molecular Neuroscience on Neurodegeneration, Graduate School of Medicine and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takuma
authors.forename: Miki
authors.initials: M
authors.lastname: Bundo
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Takaomi
authors.initials: T
authors.lastname: Saido
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; C054369:MAPT protein, human; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3